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<p>Stimulation of atypical chemokine receptor 3 (ACKR3) by chemokines does not activate G proteins but recruits arrestin. It is a chemokine scavenger that indirectly influences responses by restricting the availability of CXCL12, an agonist shared with the canonical receptor CXCR4. ACKR3 is upregulated in numerous disorders. Due to limited insights in chemokine-activated ACKR3 signaling, it is unclear how ACKR3 contributes to pathological phenotypes. One explanation may be that constitutive activity of ACKR3 drives non-canonical signaling through a basal receptor state. Here we characterize the constitutive responses of ACKR3 using inverse agonistic nanobodies to suppress its basal activity. These tools promote an inactive receptor conformation which decreased arrestin engagement and inhibited constitutive internalization. Basal non-chemotactic, cancer cell motility was also suppressed, suggesting a role for ACKR3 in this process. The basal receptor activity in pathophysiology may provide an alternate therapeutic approach for targeting ACKR3.</p>

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Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月2日

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  • Claudia V. Perez Almeria,
  • Omolade Otun,
  • Roman Schlimgen,
  • Thomas D. Lamme,
  • Lotte Di Niro,
  • Caitrin Crudden,
  • Jan Paul Bebelman,
  • Noureldine Youssef,
  • Lejla Musli,
  • Shawn Jenjak,
  • Vladimir Bobkov,
  • Julia Drube,
  • Carsten Hoffmann,
  • Brian F. Volkman,
  • Sébastien Granier,
  • Cherine Bechara,
  • Marco Siderius,
  • Raimond Heukers,
  • Christopher T. Schafer,
  • Martine J. Smit

摘要

Stimulation of atypical chemokine receptor 3 (ACKR3) by chemokines does not activate G proteins but recruits arrestin. It is a chemokine scavenger that indirectly influences responses by restricting the availability of CXCL12, an agonist shared with the canonical receptor CXCR4. ACKR3 is upregulated in numerous disorders. Due to limited insights in chemokine-activated ACKR3 signaling, it is unclear how ACKR3 contributes to pathological phenotypes. One explanation may be that constitutive activity of ACKR3 drives non-canonical signaling through a basal receptor state. Here we characterize the constitutive responses of ACKR3 using inverse agonistic nanobodies to suppress its basal activity. These tools promote an inactive receptor conformation which decreased arrestin engagement and inhibited constitutive internalization. Basal non-chemotactic, cancer cell motility was also suppressed, suggesting a role for ACKR3 in this process. The basal receptor activity in pathophysiology may provide an alternate therapeutic approach for targeting ACKR3.